Recent lung cancer research has been directed to using molecular approaches to facilitate early diagnosis, to identify clinically relevant biological factors associated with histologic heterogeneity, and to identify novel therapeutic agents. This research takes advantage of technical advances that allow rapid high throughput assays to interrogate the genome, proteome, and epigenome. In this review of gene expression profiling in lung carcinogenesis, we will focus upon recent advances in the understanding of malignant transformation of lung epithelial cells and of lung cancer differentiation and progression. These studies have provided important information about the genomic alterations of tobacco smoke-associated airway field carcinogenesis and about the developmental pathways that mediate lung tumor invasion and histologic differentiation in response to injury.